Fibrinogen is a glycoprotein present as a normal component of blood plasma, It participates in platelet aggregation and fibrin formation in the blood clotting mechanism,
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus, Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gplIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, possesses cell-attachment properties. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. (See U.S. Pat. Nos. 4,517,686; 4,589,881; and 4,661,111). Certain relatively short peptide fragments from the same molecule were found to promote cell attachment when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. (See U.S. Pat. Nos. 4,578,079 and 4,614,517).
In U.S. Pat. No. 4,683,291, inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets. U.S. Pat. No. 4,857,508 discloses tetrapeptides having utility as inhibitors of platelet aggregation.
Other synthetic peptides and their use as inhibitors of fibrinogen binding to platelets are disclosed by Koczewiak et al., Biochem. 23, 1767-1774 (1984); Plow et al., Proc. Natl. Acad. Sci. 82, 8057-8061 (1985); Ruggeri et al., Ibid. 83, 5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260 (7), 3931-3936 (1985); Haverstick et al., Blood 66 (4), 946-952 (1985); and Ruoslahti and Pierschbacher, Science 238, 491-497 (1987). Still other such inhibitory peptides are disclosed in EP Patent Applications 275,748 and 298,820.
U.S. Pat. No. 4,879,313 discloses compounds useful as inhibitors of platelet aggregation having the formula: ##STR1## wherein x=6 to 10,
y=0 to 4, PA1 z=H, COOH, CONH2 or Cl-6 alkyl, Ar=phenyl, biphenyl or naphthyl, each substituted with 1 to 3 methoxy groups, or an unsubstituted phenyl, biphenyl, naphthyl, pyridyl or thienyl group, and Asp=aspartic acid residue. PA1 2S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]butanoic acid; PA1 N-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aspartic acid, 4-(1,1-dimethylethyl)ester; PA1 N-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aspartic acid, 4-(phenylmethyl)ester; PA1 N-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aspartic acid, 4-methyl ester; PA1 N-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aspartic acid, 4-ethyl ester; PA1 N-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aspartic acid, 4-(3-propenyl) ester; PA1 N-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aspartic acid, 1-(1,1-dimethylethyl) ester; and PA1 N-[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aspartic acid, 1-phenylmethyl ester. PA1 R.sub.2 is selected from the group consisting of hydrogen, lower alkyl radicals of 1 to about 6 carbon atoms, lower alkenyl radicals of 2 to about 6 carbon atoms, and lower alkynyl radicals of 2 to about 8 carbon atoms, alicyclic hydrocarbon radicals of 3 to 6 carbon atoms, aromatic hydrocarbon radicals; wherein said radicals are optionally substituted with hydroxyl, lower alkoxy, lower alkyl, halogen, nitro, cyano, azido, ureido, ureylene, amino, trialkylsilyl, alkylsulfonyl, phenylsulfonyl, trifluoromethyl, acetoxy, acetylamino, and benzoylamino; carbonyl, carboxyl derivatives, alkylsulfonyl amino, and phenylsulfonyl amino. PA1 CHCl.sub.3 =chloroform PA1 DMF=dimethylformamide PA1 DMSO=dimethylsulfoxide PA1 g=gram PA1 MeOH=methanol PA1 min=minute PA1 h=hour PA1 mol=mole PA1 mmol=mmole PA1 MW=molecular weight PA1 TLC=thin layer chromatography PA1 NMM=N-methylmorpholine PA1 RPHPLC=Reverse Phase High Performance Liquid Chromatography PA1 TDA-1=Tris[2-(2-methoxyethoxy)ethyl]amine PA1 PTC=Phase Transfer Catalysis PA1 mL=milliliter
European Patent Application 372,486 discloses N-acyl .beta. amino acid derivatives of the formula: ##STR2## and their salts. Said compounds are useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis, and for inhibiting metastasis.
European Patent Application 381,033 discloses amidino or guanidinoaryl substituted alkanoic acid derivatives useful for the treatment of thrombosis, apoplexy, cardiac infarction, inflammation, arteriosclerosis and tumors.
European Patent Application 445,796 discloses acetic acid derivatives which have inhibitory action on the bonding of adhesive proteins to blood platelets as well as on blood platelet aggregation and cell-cell adhesion.
European Patent Application 372,486 discloses N-acyl beta amino acid derivatives and their salts. Said compounds are useful for inhibiting platelet aggregation in the treatment of thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis and for inhibiting metastasis.